Anhydrous plant-based compound antibiotic self-emulsifying ointment and preparation method thereof

Abstract

The application provides a kind of anhydrous plant-based compound antibiotic self-emulsifying ointment and a preparation method thereof.The ointment includes a compound antibiotic pharmaceutical ingredient and a plant-based semi-solid self-emulsifying base, the compound antibiotic pharmaceutical ingredient includes polymyxin antibiotic and local anesthetic analgesic ingredient, which is dissolved and uniformly dispersed in the plant-based semi-solid self-emulsifying base to form a solid solution;The plant-based semi-solid self-emulsifying base includes plant-based oil, emulsifier, co-emulsifier and thickener, and their contents are 20-70wt%, 10-30wt%, 10-35wt% and 10-20wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment respectively, and the co-emulsifier includes small molecule co-emulsifier with a molecular weight less than 100 and containing one or more active hydroxyl groups.The compound antibiotic pharmaceutical ingredient in the ointment can be well dissolved in the base to form a solid solution, has good self-emulsifying property and shear thinning property, thereby synergistically improving the rapid penetration and bacteriostatic performance of the drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a kind of anhydrous plant-based compound antibiotic self-emulsifying ointment and a preparation method thereof. BACKGROUND

[0002] Antibiotics are a class of compounds with the ability to inhibit or kill microorganisms, mainly used for the prevention and treatment of bacterial infections, including beta-lactam antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, macrolide antibiotics, quinolone antibiotics, glycopeptide antibiotics, etc. Among them, polymyxin is a kind of cyclic polypeptide antibiotic produced by the bacteria of Polymyxin genus, and the antibacterial mechanism of polymyxin is to interact with the bacterial cell membrane, destroy the integrity of the cell membrane, and thus inhibit or kill bacteria. It has broad-spectrum antibacterial activity against gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa.

[0003] Ointment formulations based on antibiotics (antibiotic ointments) have the advantages of convenient use, long residence time, good stability, etc., and are one of the ideal dosage forms for the clinical treatment of local skin infections. However, most of the ointments currently use petrolatum and liquid paraffin as the main base to disperse polymyxin antibiotics. Since petrolatum is an oily base, it has a strong greasy feeling when applied and is not easy to wash off. At the same time, considering that antibiotic active pharmaceutical ingredients and local anesthetic analgesic ingredients are generally water-soluble drugs, their solubility in low-polarity bases such as petrolatum or liquid paraffin is very poor, and there are crystals, which greatly limits the drug release capacity, resulting in poor uniformity and poor drug efficacy. Therefore, there is an urgent need to develop new compound antibiotic ointment formulations to improve the use of skin feel and improve drug release capacity. SUMMARY

[0004] To solve all or part of the above technical problems, the present application provides the following technical solutions:

[0005] One of the purposes of the present application is to provide an anhydrous plant-based compound antibiotic self-emulsifying ointment, which comprises a compound antibiotic pharmaceutical ingredient and a plant-based semi-solid self-emulsifying base, the compound antibiotic pharmaceutical ingredient comprises a polymyxin antibiotic and a local anesthetic analgesic ingredient, and the compound antibiotic pharmaceutical ingredient is dissolved and uniformly dispersed in the plant-based semi-solid self-emulsifying base to form a solid solution.

[0006] The plant-based semi-solid self-emulsifying base comprises a plant-based oil, an emulsifier, a co-emulsifier, and a thickening agent, and the content of the plant-based oil, the emulsifier, the co-emulsifier, and the thickening agent is 20-70 wt%, 10-30 wt%, 10-35 wt%, and 10-20 wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment respectively; and the co-emulsifier comprises a small-molecule co-emulsifier with a molecular weight less than 100 and containing one or more active hydroxyl groups.

[0007] The prior art generally uses a petroleum-based base (e.g., vaseline) to disperse polymyxin antibiotics to prepare an antibiotic ointment, however, the high water-soluble compound antibiotic pharmaceutical ingredients (polymyxin antibiotics and salt local anesthetic analgesic ingredients) cannot be completely dissolved in the petroleum-based base, resulting in the fact that they are dispersed in the petroleum-based base in the form of crystals, which is not conducive to the release and absorption of the polymyxin antibiotics by organisms. The anhydrous plant-based compound antibiotic self-emulsifying ointment provided by the present application contains a strong polar co-emulsifier (i.e., a small-molecule co-emulsifier with a molecular weight less than 100 and containing one or more active hydroxyl groups), so as to ensure that the high water-soluble compound antibiotic pharmaceutical ingredients are well dissolved in the ointment to form a solid solution, and the pharmaceutical ingredients in the obtained cream do not exist in the form of crystals, thereby avoiding the problem of poor release effect caused by the existence of crystals due to poor dissolution and dispersion of the pharmaceutical ingredients, so as to improve the diffusion and penetration effect of the compound antibiotic pharmaceutical ingredients and promote the absorption of the compound antibiotic pharmaceutical ingredients by organisms.

[0008] The self-emulsifying base adopted by the present application can self-emulsify to form smaller emulsion droplets when encountering an environmental solution (e.g., surface exudate of a wound), thereby further improving the penetration performance. The ointment is smoother and easier to apply, and the greasy feeling is greatly improved compared with the vaseline base. The excellent compound antibiotic pharmaceutical ingredient dispersibility and self-emulsifying properties of the ointment synergistically improve the diffusion and penetration effect of the compound antibiotic pharmaceutical ingredients in the ointment, thereby exhibiting good antibacterial effect. In addition, the self-emulsifying ointment provided by the present application does not contain water, which on the one hand ensures the self-emulsifying effect of the ointment when applied, and on the other hand avoids the problem of degradation of polymyxin antibiotics in the presence of water.

[0009] In some embodiments, the content of the compound antibiotic pharmaceutical ingredients is 0.4-10 wt%.

[0010] In some embodiments, the content of the polymyxin antibiotics is 0.1-2.5 wt%.

[0011] In some embodiments, the content of the local anesthetic analgesic ingredients is 0.3-7.5 wt%, preferably 4 wt%.

[0012] In some embodiments, the polymyxin antibiotics comprise a combination of one or more of bacitracin, zinc bacitracin, neomycin sulfate, and polymyxin B sulfate.

[0013] In some embodiments, the polymyxin antibiotic includes bacitracin and / or zinc bacitracin, neomycin sulfate, and polymyxin B sulfate, and the content of the bacitracin and / or zinc bacitracin, neomycin sulfate, and polymyxin B sulfate is 0.07wt%-1.6wt%, 0.03wt%-0.8wt%, and 0.01wt%-0.25wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment, respectively.

[0014] In some preferred embodiments, the polymyxin antibiotic includes bacitracin, neomycin sulfate, and polymyxin B sulfate, and the content of the bacitracin, neomycin sulfate, and polymyxin B sulfate is 0.83wt%, 0.35wt%, and 0.12wt% of the anhydrous plant-based compound antibiotic self-emulsifying ointment, respectively.

[0015] In some embodiments, the salt local anesthetic pain-relieving component includes a caine drug.

[0016] In some embodiments, the salt local anesthetic pain-relieving component includes one or a combination of lidocaine, lidocaine hydrochloride, procaine hydrochloride, or bupivacaine.

[0017] In some embodiments, the small molecule co-emulsifier can dissolve the polymyxin antibiotic, and the small molecule co-emulsifier includes one or a combination of 1,2-propanediol (PG), 1,3-propanediol, ethanol, and glycerol.

[0018] In some embodiments, the mass of the small molecule co-emulsifier is more than 30wt% of the total mass of the co-emulsifier, for example, 30wt%-100wt%.

[0019] In some embodiments, in addition to the small molecule co-emulsifier described above, the co-emulsifier can also include a low-polarity co-emulsifier, for example, polyethylene glycol 400, ethoxydiglycol, and the like, to adjust the overall viscosity of the ointment.

[0020] In some embodiments, the plant-based oil includes one or a combination of oleyl alcohol (OA), medium-chain triglyceride (GTCC), isopropyl myristate (IPM), cocoyl octanoic acid ester (3C), or glyceryl triacetate (GTA).

[0021] In some embodiments, the emulsifier includes one or a combination of polyoxyethylene 40 hydrogenated castor oil (RH40), polyoxyethylene (35) castor oil (ELP), polysorbate 20 (PS20), polysorbate 80 (PS80), polyethylene glycol cetostearyl alcohol ether 20 (CS20), or poloxamer 188 (P188).

[0022] In some embodiments, the thickening agent comprises a combination of one or more of glycerol monostearate II (GMS II), poloxamer 407 (P407), octadecanol, or octadecanoic acid.

[0023] In some embodiments, the anhydrous plant-based compounded antibiotic self-emulsifying ointment has a viscosity of 402-4638 -1 at a shear rate of 0.1 s , and a viscosity of 1-6 -1 at a shear rate of 100 s . That is, the ointment provided herein has good shear thinning property.

[0024] A second object of the present application is to provide a preparation method of an anhydrous plant-based compounded antibiotic self-emulsifying ointment, comprising:

[0025] mixing the plant-based oil, the emulsifier, the co-emulsifier, and the thickening agent, and stirring at a temperature of 55-100°C until a homogeneous phase is formed to obtain a plant-based semi-solid self-emulsifying base;

[0026] mixing at least the compounded antibiotic pharmaceutical ingredient with the plant-based semi-solid self-emulsifying base, the compounded antibiotic pharmaceutical ingredient comprising a polymyxin antibiotic and a local anesthetic analgesic ingredient, so that the compounded antibiotic pharmaceutical ingredient is dissolved in the plant-based semi-solid self-emulsifying base to form a solid solution, thereby obtaining an anhydrous plant-based compounded antibiotic self-emulsifying ointment;

[0027] wherein the plant-based oil, the emulsifier, the co-emulsifier, and the thickening agent are used in an amount of 20-70wt%, 10-30wt%, 10-35wt%, and 10-20wt% of the anhydrous plant-based compounded antibiotic self-emulsifying ointment, respectively; and the co-emulsifier comprises a small molecule co-emulsifier with a molecular weight less than 100 and containing one or more active hydroxyl groups.

[0028] In some embodiments, the stirring time at a temperature of 55-100°C is 20-60 min.

[0029] In some preferred embodiments, the preparation method comprises mixing the plant-based oil, the emulsifier, the co-emulsifier, and the thickening agent, and stirring at a temperature of 70°C for 30 min to obtain a plant-based semi-solid self-emulsifying base.

[0030] Compared with the prior art, the application has at least the following beneficial effects: the compound antibiotic drug components (i.e. polymyxin antibiotics and local anesthetic pain-relieving components) in the anhydrous plant-based compound antibiotic self-emulsifying ointment provided by the application can be dissolved in the plant-based semi-solid self-emulsifying matrix to form a solid solution, without crystals, thereby improving the dispersion uniformity of the active components and facilitating their absorption by organisms, and solving the problems of the petroleum-based matrix (e.g. vaseline) in the prior art, i.e. the inability to completely dissolve active components such as polymyxin antibiotics and uncontrollable dosage; the ointment provided by the application can spontaneously emulsify to generate smaller emulsion droplets and quickly penetrate, and the good dispersion of the antibiotics and the self-emulsifying property of the ointment synergistically improve the drug diffusion and penetration effect. BRIEF DESCRIPTION OF DRAWINGS

[0031] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or the prior art description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments described in the present application, and other drawings can also be obtained by those skilled in the art without creative labor on the basis of these drawings.

[0032] Figure 1 is a photo of the anhydrous plant-based semi-solid self-emulsifying matrix prepared in the present application examples 1-14;

[0033] Figure 2 is a photo of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in the present application examples 1-14;

[0034] Figure 3 、 Figure 4 、 Figure 5 are photos of the anhydrous plant-based compound antibiotic self-emulsifying ointments prepared in the present application examples 15, 16 and 17, respectively;

[0035] Figure 6 is a photo of the anhydrous plant-based semi-solid self-emulsifying ointment prepared in the present application comparative examples 1-3, compared with example 1, only the different co-emulsifiers are changed (left photo: polyethylene glycol 400, middle: PE / L 44, right photo: ethoxydiglycol);

[0036] Figure 7 is the optical microscope images at 0 degrees (a) and 45 degrees (b) and the corresponding polarized light microscope images (c, d) of the commercially available Neosporin ointment in the present application comparative example 5;

[0037] Figure 8 is the optical microscope images at 0 degrees (a) and 45 degrees (b) and the corresponding polarized light microscope images (c, d) of the commercially available compound polymyxin B ointment in the present application comparative example 6;

[0038] Figure 9 are optical microscope images at 0 degree (a) and 45 degree (b) and corresponding polarized light microscope images (c, d) of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 1 of the present application;

[0039] Figure 10 are optical microscope images at 0 degree (a) and 45 degree (b) and corresponding polarized light microscope images (c, d) of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 2 of the present application;

[0040] Figure 11 are optical microscope images at 0 degree (a) and 45 degree (b) and corresponding polarized light microscope images (c, d) of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 3 of the present application;

[0041] Figure 12 are optical microscope images at 0 degree (a) and 45 degree (b) and corresponding polarized light microscope images (c, d) of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 4 of the present application;

[0042] Figure 13 are optical microscope images at 0 degree (a) and 45 degree (b) and corresponding polarized light microscope images (c, d) of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Example 5 of the present application;

[0043] Figure 14 are the "viscosity-shear rate" change curve graphs of the samples of Examples 1-5, Comparative Example 5, Comparative Example 6 of the present application;

[0044] Figure 15 are the pictures of the E. coli inhibition zone experiment results of the samples of Examples 1-5 and Comparative Examples 4-6 (compound polymyxin-vaseline base, commercially available compound polymyxin B ointment and Neosporin);

[0045] Figure 16 are the pictures of the S. aureus inhibition zone experiment results of the samples of Examples 1-5 and Comparative Examples 4-6 (compound polymyxin-vaseline base, commercially available compound polymyxin B ointment and Neosporin);

[0046] Figure 17 are the statistical results of the E. coli inhibition zone area of the samples of Examples 1-5 and Comparative Examples 4-6 (compound polymyxin-vaseline base, commercially available compound polymyxin B ointment and Neosporin);

[0047] Figure 18The results of the statistical analysis of the inhibition zone areas of the Staphylococcus aureus of the samples of the present application (Examples 1-5) and the comparative examples (Comparative Examples 4-6) (compound polymyxin-vaseline base, commercially available compound polymyxin B ointment and Neosporin) are shown in Table 1. DETAILED DESCRIPTION

[0048] The technical solutions of the present application are described in detail below with reference to specific examples, so that those skilled in the art can better understand and implement the technical solutions of the present application. The specific functional details disclosed herein should not be interpreted as limiting, but only as a basis for the claims and for teaching those skilled in the art to employ the representative basis of the present application in different ways in any appropriate detailed implementation.

[0049] Unless otherwise specified, the raw materials and reagents used in the present application are commercially available.

[0050] Example 1

[0051] Example 1 provides a water-free plant-based compound antibiotic self-emulsifying ointment and a preparation method thereof, which specifically comprises the following steps:

[0052] Weigh isopropyl myristate (IPM), 1,2-propanediol (PG), polyoxyethylene 40 hydrogenated castor oil (RH40) and glycerol monostearate II (GMS II), heat and stir at 70 ℃ for 30 min until a homogeneous phase is obtained, to obtain a plant-based semi-solid self-emulsifying base;

[0053] Disperse 0.83wt% bacitracin, 0.35wt% neomycin sulfate, 0.12wt% polymyxin B sulfate and 4wt% lidocaine hydrochloride, which are compound antibiotic drug components, uniformly into the plant-based semi-solid self-emulsifying base prepared above, and stir until a homogeneous solid is obtained, to obtain a water-free plant-based compound antibiotic self-emulsifying ointment; wherein the weight percentages of IPM, PG, RH40 and GMS II in the ointment are 49.1wt%, 25.2wt%, 10.2wt% and 10.2wt%, respectively.

[0054] Examples 2-14

[0055] Examples 2-14 differ from Example 1 only in that the plant-based oil, emulsifier, co-emulsifier and thickening agent are changed according to Table 1, and the weight percentages of the corresponding materials are the same as in Example 1.

[0056] Table 1: Components and weight percentages of the water-free plant-based compound antibiotic self-emulsifying ointments in Examples 1-14

[0057]

[0058] The photos of the plant-based semi-solid self-emulsifying base, the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in all of the examples 1-14 are shown in Figs. 1-14, respectively. All of the samples present uniform and stable solid paste. Figure 1 and Figure 2

[0059] Example 15

[0060] The oleyl alcohol (OA), 1,2-propanediol (PG), polyoxyethylene (35) castor oil (ELP) and glycerol monostearate II (GMS II) were weighed and mixed, heated and stirred at 70 °C for 30 min until a uniform phase was obtained, to obtain a plant-based semi-solid self-emulsifying base;

[0061] The 0.075wt% bacitracin, 0.03wt% neomycin sulfate, 0.01wt% polymyxin B sulfate and 0.36wt% lidocaine hydrochloride were uniformly dispersed into the plant-based semi-solid self-emulsifying base prepared above, and stirred until a uniform solidification was obtained, to obtain an anhydrous plant-based compound antibiotic self-emulsifying ointment; wherein the weight ratio of OA, PG, ELP and GMS II in the ointment is 60.9%, 13.425%, 12.6% and 12.6%, respectively.

[0062] Figure 3 Fig. 15 is a photo of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in the example 15 of the present application.

[0063] Example 16

[0064] The oleyl alcohol (OA), 1,2-propanediol (PG), polyoxyethylene (35) castor oil (ELP) and glycerol monostearate II (GMS II) were weighed and mixed, heated and stirred at 70 °C for 30 min until a uniform phase was obtained, to obtain a plant-based semi-solid self-emulsifying base;

[0065] The 1.49wt% bacitracin, 0.63wt% neomycin sulfate, 0.22wt% polymyxin B sulfate and 7.2wt% lidocaine hydrochloride were uniformly dispersed into the plant-based semi-solid self-emulsifying base prepared above, and stirred until a uniform solidification was obtained, to obtain an anhydrous plant-based compound antibiotic self-emulsifying ointment; wherein the weight ratio of OA, PG, ELP and GMS II in the ointment is 54.7%, 12.96%, 11.4% and 11.4%, respectively.

[0066] Figure 4 Fig. 16 is a photo of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in the example 16 of the present application.

[0067] Example 17

[0068] ​Take oleic acid (OA), 1,2-propanediol (PG), polyoxyethylene (35) castor oil (ELP) and glycerol monostearate II (GMS II) mixture, 70 ℃ heating stirring 30 min, to uniform phase, get plant-based semi-solid self-emulsifying base;

[0069] 0.75wt% of bacitracin, 0.32wt% of neomycin sulfate, 0.11wt% of polymyxin B sulfate and 3.6wt% of procaine hydrochloride are uniformly dispersed into the plant-based semi-solid self-emulsifying base prepared above, and stirred to uniform solidification to obtain anhydrous plant-based compound antibiotic self-emulsifying ointment; wherein the weight ratio of OA, PG, ELP and GMS II in the ointment is 58.3%, 12.72%, 12.1% and 12.1% respectively.

[0070] Figure 5 It is the photo of the anhydrous plant-based compound antibiotic self-emulsifying ointment prepared in Example 17.

[0071] Comparative Example 1

[0072] The difference between Comparative Example 1 and Example 1 is only that the strong polar small molecule co-emulsifier 1,2-propanediol (PG) in Example 1 is replaced by low polarity polyethylene glycol 400, and the rest is the same as Example 1.

[0073] Comparative Example 2

[0074] The difference between Comparative Example 2 and Example 1 is only that the strong polar small molecule co-emulsifier 1,2-propanediol (PG) in Example 1 is replaced by low polarity PE / L 44 (a kind of ethylene oxide / propylene oxide block copolymer), and the rest is the same as Example 1.

[0075] Comparative Example 3

[0076] The difference between Comparative Example 3 and Example 1 is only that the strong polar small molecule co-emulsifier 1,2-propanediol (PG) in Example 1 is replaced by low polarity ethoxydiglycol, and the rest is the same as Example 1.

[0077] Figure 6 It is the photo of the ointment prepared in Comparative Examples 1-3, and the results show that after replacing the strong polar co-emulsifier with a low polar co-emulsifier, the active pharmaceutical ingredients are precipitated at the bottom and cannot be uniformly dissolved and dispersed.

[0078] Comparative Example 4

[0079] The difference between Comparative Example 4 and Example 1 is only that the plant-based semi-solid self-emulsifying base in Example 1 is replaced by vaseline, and the rest is the same as Example 1.

[0080] Comparative Example 5

[0081] Commercial products:

[0082] Neosporin: bacitracin zinc (0.7 wt%), neomycin sulfate (0.35 wt%), polymyxin B sulfate (0.12 wt%), pramoxine hydrochloride (1 wt%), and the rest is base petrolatum.

[0083] Comparative Example 6

[0084] Commercial products:

[0085] Compound Polymyxin B Ointment: bacitracin (0.83 wt%), neomycin sulfate (0.35 wt%), polymyxin B sulfate (0.06 wt%), lidocaine hydrochloride (4 wt%), and the rest is base petrolatum.

[0086] The ointments of the above examples and comparative examples were evaluated for drug dispersibility, viscosity, and bacteriostatic effect, and the evaluation methods and results are as follows:

[0087] 1. Sample dispersibility evaluation of anhydrous plant-based compound antibiotic self-emulsifying ointment, Comparative Example 5, and Comparative Example 6

[0088] The anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1-5, the Neosporin sample of Comparative Example 5, and the compound polymyxin B ointment sample of Comparative Example 6 were observed using the optical mode and the polarized mode of a microscope.

[0089] Method of operation: Take a small amount of the above sample, place it on a glass slide, gently cover it with a cover glass, then place it under a microscope, and observe it using the optical mode and the polarized mode (0° and 45°) of the microscope, respectively, and take photos.

[0090] Figure 7 is the optical microscope image at 0 degrees (a) and 45 degrees (b) and the corresponding polarized microscope image (c, d) of the commercial Neosporin ointment in Comparative Example 5 of the present invention. Figure 8 is the optical microscope image at 0 degrees (a) and 45 degrees (b) and the corresponding polarized microscope image (c, d) of the commercial compound polymyxin B ointment in Comparative Example 6 of the present invention. Figure 9 、 Figure 10 、 Figure 11 、 Figure 12 、 Figure 13 are the optical microscope images at 0 degrees (a) and 45 degrees (b) and the corresponding polarized microscope images (c, d) of the anhydrous plant-based compound antibiotic self-emulsifying ointments of Examples 1-5 of the present invention, respectively. As Figure 7 and Figure 8As shown, the commercially available Neosporin and compound polymyxin B ointment have obvious crystal particles under the microscope. At the same time, there is obvious bright-dark alternation difference from 0° to 45° in the polarized mode, proving the existence of drug crystals, i.e. the poor dispersibility of the drug in the ointment preparation matrix. While the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared based on Examples 1-5 are not observed to have bright-dark changes from 0° to 45° in the polarized mode of the microscope, as shown, proving that there are no crystals of the drug in the corresponding preparation matrix, and the dispersibility is good. The above phenomenon shows that the good dispersibility of the antibiotic drug can be achieved based on the technical scheme of the present application, and the dispersing effect is better than that of the commercially available products. Figure 9 to Figure 13

[0091] 2. Viscosity evaluation of the samples of the anhydrous plant-based compound antibiotic self-emulsifying ointment, Comparative Example 5 and Comparative Example 6

[0092] The "viscosity-shear rate" changes of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1-5, the Neosporin of Comparative Example 5 and the compound polymyxin B ointment of Comparative Example 6 were tested using a rotational rheometer.

[0093] Operation method: a small amount of the above sample was taken and placed on a 20 mm 0° flat plate, the Flow-ramp mode was used, the gap value was set to 500 μm, the temperature was 25 °C, and the shear rate was 0.1-100 s -1 . The "viscosity-shear rate" change curve was obtained by testing.

[0094] Figure 14 is the "viscosity-shear rate" change curve of the samples of Examples 1-5, Comparative Example 5 and Comparative Example 6. As can be seen from Figure 14 , the viscosity of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1-5 can basically cover the two commercially available products. The viscosity at low shear rate reflects the storage stability of the sample, such as when the shear rate is 0.1 s -1 , the viscosity of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1-5 is 402-4638 , the viscosity of Neosporin is 848 , and the viscosity of compound polymyxin B is 3518 ; the viscosity at high shear rate reflects the coatability of the sample, such as when the shear rate is about 100 s -1 , the viscosity of the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1-5 is 1-6 , the viscosity of Neosporin is 4 , and the viscosity of compound polymyxin B is 15 ​The sample of Example 5 has higher viscosity under low shear rate condition than the commercial product, and has lower viscosity under high shear rate condition than the commercial product, and is easier to apply. (The shear rate for applying the hand cream / cream is 10 2 ~10 4 s -1 )。

[0095] 3. Evaluation of the bacteriostatic effect of the anhydrous plant-based compound antibiotic self-emulsifying ointment of Examples 1-5 and the samples of Comparative Examples 4-6

[0096] The bacteriostatic circle experiment was performed on the anhydrous plant-based compound antibiotic self-emulsifying ointment samples prepared in Examples 1-5, Neosporin of Comparative Example 5, and compound polymyxin B ointment of Comparative Example 6, photos of the bacteriostatic effect were taken, and the area of the bacteriostatic circle was calculated using Image J software.

[0097] Operation method: S1. Prepare sterilized TSA solid medium; S2. Activate the bacterial strain (Escherichia coli, E. E. coli and Staphylococcus aureus, S. aureus ) one day in advance; S3. Measure the OD value of the test bacterial solution, dilute to 1x10 6 CFU / ml; S4. Take 100 μl of the diluted bacterial solution and add it to the TSA solid medium, and use sterilized glass beads to disperse it evenly, then pour out the glass beads; S5. Use a sterilized gun head to punch a hole at the top, fill the sample to ensure consistent sample addition; S6. Place it in a 37 ℃ constant temperature incubator and incubate overnight, observe the bacteriostatic circle results, take photos and use ImageJ software to calculate the area of the bacteriostatic circle.

[0098] Figure 15 is the picture of the bacteriostatic circle experiment results of the samples of Examples 1-5 and Comparative Examples 4-6 on Escherichia coli. Figure 16 is the picture of the bacteriostatic circle experiment results of the samples of Examples 1-5 and Comparative Examples 4-6 on Staphylococcus aureus. According to Figure 15 and Figure 16 , the samples prepared based on the technical solutions of the present application have stronger bacteriostatic ability on Escherichia coli and Staphylococcus aureus.

[0099] Figure 17 is the statistical results of the bacteriostatic circle area of the samples of Examples 1-5 and Comparative Examples 4-6 on Escherichia coli. Figure 18 is the statistical results of the bacteriostatic circle area of the samples of Examples 1-5 and Comparative Examples 4-6 on Staphylococcus aureus. According to Figure 17 and Figure 18It can be seen that the water-free plant-based compound antibiotic self-emulsifying ointment samples prepared based on Examples 1-5 have larger bacterial inhibition zone areas than Comparative Examples 4-6 for the two bacteria. The compound polymyxin B ointment needle of Comparative Example 5 has a bacterial inhibition zone area of 1.8 cm for E. coli 2 The Neosporin of Comparative Example 6 has a bacterial inhibition zone area of 1.3 cm for E. coli 2 While the water-free plant-based compound antibiotic self-emulsifying ointment samples prepared based on Examples 1-5 have bacterial inhibition zone areas of 4.9 cm 2 , 5.7 cm 2 , 4.9 cm 2 , 4.4 cm 2 and 5.0 cm 2 for E. coli, respectively. The compound polymyxin B ointment needle of Comparative Example 5 has a bacterial inhibition zone area of 2.4 cm for S. aureus 2 The Neosporin of Comparative Example 6 has a bacterial inhibition zone area of 1.7 cm for S. aureus 2 While the water-free plant-based compound antibiotic self-emulsifying ointment samples prepared based on Examples 1-5 have bacterial inhibition zone areas of 6.2 cm 2 , 5.9 cm 2 , 5.0 cm 2 , 6.0 cm 2 and 5.8 cm 2 for S. aureus, respectively. The possible reason is that the self-emulsifying base can self-emulsify with the exudate on the wound surface, thereby promoting drug release, and thus showing better antibacterial effect than the commercially available products.

[0100] Aspects, embodiments, features, and examples of the present application should be considered in all respects as illustrative only and not restrictive, the scope of the present application being defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed application.

[0101] In addition, the present inventors have also carried out tests with other raw materials, process operations, and process conditions described in the present specification with reference to the foregoing examples, and all have obtained relatively ideal results.

[0102] While the application has been described with reference to the illustrative embodiments, those skilled in the art will understand that various other changes, omissions, and / or additions can be made without departing from the spirit and scope of the application. Further, many modifications can be made to adapt a particular situation or material to the teachings of the application without departing from its scope. Therefore, it is intended that the application not be limited to the disclosed embodiments, but will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated otherwise, any use of the terms first, second, etc., does not denote any ordinal, or importance, but merely distinguishes one element from another.

Claims

1. An anhydrous plant-based compounded antibiotic self-emulsifying ointment, characterized by: The anhydrous plant-based compound antibiotic self-emulsifying ointment comprises a compound antibiotic pharmaceutical ingredient and a plant-based semi-solid self-emulsifying base, the compound antibiotic pharmaceutical ingredient is highly water-soluble, which comprises a polymyxin antibiotic and a local anesthetic analgesic ingredient, the polymyxin antibiotic comprises 0.07wt%-1.6wt% bacitracin and / or zinc bacitracin, 0.03wt%-0.8wt% neomycin sulfate and 0.01wt%-0.25wt% polymyxin B sulfate, respectively, of the total mass of the anhydrous plant-based compound antibiotic self-emulsifying ointment, and the local anesthetic analgesic ingredient comprises 0.3~7.5wt% lidocaine hydrochloride of the total mass of the anhydrous plant-based compound antibiotic self-emulsifying ointment; The compound antibiotic pharmaceutical ingredient is dissolved and uniformly dispersed in the plant-based semi-solid self-emulsifying base to form a solid solution; wherein the plant-based semi-solid self-emulsifying base comprises 20-70wt% plant-based oil, 10-30wt% emulsifier, 10-35wt% 1,2-propanediol and 10-20wt% thickening agent, respectively, of the total mass of the anhydrous plant-based compound antibiotic self-emulsifying ointment; and the plant-based oil is selected from one or a combination of more than one of oleyl alcohol, medium-chain triglyceride, isopropyl myristate, cocoyl octanoic acid decanoate or glyceryl triacetate, the emulsifier is selected from one or a combination of more than one of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene (35) castor oil, polysorbate 20, polysorbate 80, polyethylene glycol hexadecyl octadecyl ether 20 or poloxamer 188, and the thickening agent is selected from one or a combination of more than one of monodouble stearic acid glyceride II, poloxamer 407, octadecanol or octadecanoic acid.

2. The anhydrous plant based multi-antibiotic self-emulsifying soft creme as claimed in claim 1 wherein: The total content of the polymyxin antibiotic is 0.1~2.5wt%.

3. The anhydrous plant based multi-antibiotic self-emulsifying soft creme as claimed in claim 1 wherein: The plant-based semi-solid self-emulsifying base further comprises ethoxydiglycol and / or PEG400.

4. The anhydrous plant based multi-antibiotic self-emulsifying soft creme as claimed in claim 1, wherein: The anhydrous plant-based compound antibiotic self-emulsifying ointment has a viscosity of 402-4638 -1 at a shear rate of 0.1 s , 100 s -1 he viscosity is 1-6 at a shear rate of 100 s 5. The anhydrous plant based compound antibiotic self-emulsifying ointment as claimed in claim 1 wherein, The preparation method comprises: Mixing the plant-based oil, emulsifier, 1,2-propanediol and thickening agent, and stirring at a temperature of 55℃-100℃ until a uniform phase is formed to obtain a plant-based semi-solid self-emulsifying base; Mixing at least the compound antibiotic pharmaceutical ingredient and the plant-based semi-solid self-emulsifying base, dissolving the compound antibiotic pharmaceutical ingredient in the plant-based semi-solid self-emulsifying base to form a solid solution, and obtaining an anhydrous plant-based compound antibiotic self-emulsifying ointment.

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